1. Field of the Invention
This invention relates to the immune system. Specifically, the invention provides the use of a cytokine, interleukin-10 (IL-10), to inhibit viral replication.
2. Background Art
The cytokine IL-10 (previously called cytokine synthesis inhibitory factor) was initially identified in 1989 as a factor secreted by murine Th2 cell clones that inhibits the secretion of interferon gamma (IFN-.gamma.) and other cytokines by Th1 cells (1). In addition, IL-10 appears to mediate some of the B cell stimulatory effects of Th2 cells, and this cytokine thus appears to be involved in shifting the balance of an immune response away from cellular and towards humoral immunity (2, 3). Additional studies have shown IL-10 to have immunomodulatory effects by acting on macrophages and other cell types. In particular, IL-10 suppresses the secretion of various cytokines by activated macrophages (4, 5), costimulates mast cell growth (6), and costimulates thymocyte growth in the presence of IL-2 and/or IL-4 (7).
Soon after the discovery of murine IL-10, the human IL-10 gene was identified and cloned (8). Human IL-10, which has activities similar to that of murine IL-10, has been found to be produced by cells of several lineages including B lymphocytes (9, 10) and monocyte/macrophages (M/M) (5, 11). Human and murine IL-10 were found to exhibit extensive sequence homology to BCRF-1, a previously uncharacterized open reading frame in the genome of Epstein Barr virus (EBV) (8). Moreover, this viral protein was found to retain a number of IL-10 activities (12). It has been speculated that BCRF1 may be a "trapped" cellular genes that may confer a selective advantage to EBV, perhaps by directly contributing to the stimulation of EBV-infected B cells, or by helping the EBV-infected cells evade immune surveillance (13, 14).
It has also been suggested that a dysregulation between Th1 and Th2 cells, perhaps in part mediated by IL-10, might contribute to the pathogenssis of acquired immunodeficiency (AIDS). In a murine experimental model for AIDS induced by LP-BM5 murine leukemia virus, IL-10 overexpression has been found to correlate with a shift towards Th2 helper cells, B cell hyperactivation, down-regulation of Th1 cytokine secretion, and impaired CD8+ T cell function (15). Recent data from patients infected with human immunodeficiency virus (HIV) suggest that disease progression is associated with increased secretion of Th2 cytokines and downregulation of Th1 cytokines (16).
In the case of parasitic infections, it has been noted that IL-10 inhibits the production of reactive nitrogen oxides, which are involved in the elimination of intracellular Toxoplasma gondii (30) and the extracellular killing of Schistosoma mansoni by macrophages (30-32). It has been speculated that induction of IL-10 production may be a means by which parasites escape cell-mediated immunity (33).
In a murine retroviral model of AIDS, there is evidence to suggest that overexpression of IL-10 may contribute to disease pathogenesis by simultaneously suppressing cellular immunity and stimulating B cell hyperactivity (15).
These data suggest that IL-10 overexpression may be advantageous to vital replication and may actually contribute to disease progression. Contrary to these data, the present invention provides that IL-10 can actually be used to inhibit viral replication, especially the replication of HIV in human monocytes, macrophages or monocyte derived cells. Thus, the invention provides an urgently needed means to prevent HIV replication and treat diseases caused by HIV.